Synthesis of 1,3,4-Trisubstituted and 1,3,4,5-Tetrasubstituted Pyrazoles

ABSTRACT

This invention concerns the synthesis of highly substituted pyrazoles, which are structural components of pharmacological compounds, through reaction of hydrazones with nitroolefins.

This application claims the benefit of U.S. provisional patent application Ser. No. 60/976,907, filed on Oct. 2, 2007, which is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to methods for the regioselective synthesis of highly substituted pyrazoles from hydrazones and nitroolefins.

BACKGROUND OF THE INVENTION

Pyrazoles are an important class of compounds in the pharmaceutical industry. Compounds containing the pyrazole motif are being developed for a wide range of therapeutic areas including CNS, metabolic diseases and endocrine functions and oncology (Elguero, J. et al. Targets in Heterocyclic Systems 2002, 6, 52-98 and reference cited therein). Several pyrazoles have been successfully commercialized, such as the blockbuster drugs sildenafil, celecoxib, and rimonabant:

Substituted pyrazoles have also been applied as novel ligands for transition metal-catalyzed cross-coupling reactions ((a) Singer, R. A. et al. Synthesis 2003, 1727-1732; (b) Singer, R. A. et al. Tetrahedron Lett. 2006, 47, 3727-3731). The synthesis of multi-substituted pyrazoles has been extensively studied, and two methods have certainly stood out in terms of generality and convenience ((a) Elguero, J. Comp. Heterocycl. Chem. 1984, 5, 167; (b) Elguero, J. Comp. Heterocycl. Chem. II 1996, 3, 1-75, 817-932; (c) Makino, K. et al. J. Heterocyl. Chem. 1998, 35, 489-497). One is the venerable Knorr reaction involving the condensation of substituted hydrazines with 1,3-diketones or their derivatives (Scheme 1A) ((a) Knorr, L. Ber. 1883, 16, 2587; (b) Patel, M. V. et al. J. Org. Chem. 2004, 69, 7058-7065; (c) Peruncheralathan, S. et al. J. Org. Chem. 2005, 70, 10030-10035).

The other method is the 1,3-dipolar cycloaddition of diazoalkanes or nitrile imines with olefins or alkynes (Scheme 1B) ((a) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 565-632; (b) Padwa, A. 1,3-Dipolar Cycloaddition Chemistry; John Wiley & Sons: New York, 1984; Vol. I; (c) Padwa, A.; Pearson, W. H.; Eds. Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products; John Wiley & Sons: New York, 2002).

As successful as these two methods are in preparing pyrazoles with various substitution patterns, they are not particularly suited for the regioselective synthesis of 1,3,4-trisubstituted pyrazoles. 1,3,4-Trisubstituted pyrazoles are pharmaceutically important, yet less represented in the literature, probably due to synthetic difficulties ((a) Kira, M. A. et al. Tetrahedron Lett. 1969, 2, 109-110; (b) Stauffer, S. R. et al. Bioorg. Med. Chem. 2001, 9, 141-150; (c) Bekhit, A. A. et al. Bioorg. Med. Chem. 2004, 12, 1935-1945; (d) De Paulis, T. et al. J. Med. Chem. 2006, 49, 3332-3344). In the Knorr reaction, the condensation of substituted hydrazines with β-ketoaldehydes usually favors 1,4,5-trisubstituted pyrazoles ((a) Robertson, I. R. et al. Tetrahedron 1984, 40, 3095-3112; (b) Subramanian, L. M. et al. Synthesis 1984, 12, 1063-1065; (c) Press, J. B. et al. J. Heterocycl. Chem. 1985, 22, 561-4; (d) Muthusubramanian, L. et al. Eur. J. Med. Chem. 1986, 21, 163-166; (e) Singh, K. et al. J. Chem. Res. 2005, 8, 526-529). One solution to this issue is to prepare a 3,4-disubstituted pyrazole with hydrazine and then introduce the N-1 substituent, but this method is often not regioselective ((a) Meanwell, N. A. et al. J. Med. Chem. 1992, 35, 389-397; (b) Wang, X. et al. Org. Lett. 2000, 2, 3107-3109; (c) Patel, M. V. et al., 2004).

On the other hand, 1,3-dipolar cycloaddition reactions have been successfully employed to synthesize 1,3,4-trisubstituted pyrazoles, usually regioselectively ((a) Fathi, T. et al. Tetrahedron 1988, 44, 4527-4536; (b) Daou, B. et al. J. Heterocycl. Chem. 1989, 26, 1485-1488; (c) Lokanatha Rai, K. M. et al. Synth. Commun. 1989, 19, 2799-2807; (d) Abdallah, M. A. et al. J. Chem. Res. Syn. 1994, 2, 76-77; (e) Del Valle, J. L. et al. J. Heterocycl. Chem. 1995, 32, 899; (f) Liu, B. et al. Tetrahedron Lett. 1999, 40, 7399; (g) Molteni, G. et al. Chem. Eur. J. 2003, 9, 2770; (h) Dawood, K. M.; et al. J. Org. Chem. 2005, 70, 7537-7541). However, the difficulty generating and handling the reactive 1,3-dipoles often limits their synthetic utility. Furthermore, an additional oxidation step is often required to transform the pyrazolidine adduct to the pyrazole product.

Recently, a regioselective synthesis of 1,3,5-trisubstituted pyrazoles through reactions of hydrazones with nitroolefins under either neutral (heating in methanol (MeOH) or ethylene glycol) or acidic conditions (trifluoroacetic acid (TFA) in CF₃CH₂OH) was reported (Scheme 2, reaction A) (Deng, X.; Mani, N. S. Org. Lett. 2006, 8, 3505-3508). Excellent 1,3,5-regioselectivity was achieved, presumably because the aniline nitrogen atom of the hydrazone is more nucleophilic than the benzylic carbon atom, thus attacking nitroolefin preferentially. In the context of the present invention, it was hypothesized that by modulating the relative nucleophilicities of the nitrogen and the carbon atoms of the hydrazone, a novel 1,3,4-selectivity might instead be achieved. In the literature, it has been shown that the reaction of nitroolefins with diazoalkanes, in which the carbon atom is more nucleophilic, affords 3,4-disubstituted pyrazoles ((a) Parham, W. E. et al. J. Am. Chem. Soc. 1950, 72, 3843-3846; (b) Mancera, M. et al. J. Org. Chem. 1988, 53, 5648-5651; (c) Aggarwal, V. K. et al. J. Org. Chem. 2003, 68, 5381-5383). In addition, 1,3,4-trisubstituted pyrazoles were obtained as minor products from the reaction of hydrazones with nitroolefins under microwave conditions (Arrieta, A. et al. Tetrahedron 1998, 54, 13167-1318).

Based on the limitations of literature methods and the prevalence of highly substituted pyrazole components in pharmaceutical agents, a general, convenient method in the synthesis of 1,3,4-substituted pyrazoles is highly desirable. Herein, we report a novel, regioselective synthesis of 1,3,4-trisubstituted and 1,3,4,5-tetrasubstituted pyrazoles from readily available hydrazones and nitroolefins under basic conditions. This reaction is quite general for a range of substrates, and has broad functional group compatibility.

SUMMARY OF THE INVENTION

In one aspect the invention relates to a process for the preparation of compounds of Formula (I) and salts thereof:

comprising

-   (a) reacting a hydrazone of formula (II):

with a nitroolefin of formula (III):

in the presence of a strong base, in a polar, aprotic organic solvent; and

-   (b) quenching the reaction with a strong acid;     wherein -   R¹ is C₁₋₆alkyl, or an aryl group unsubstituted or substituted with     one or two R^(a) substituents;     -   where each R^(a) is independently —OH, —OC₁₋₆alkyl, —CN,         —N(R^(b))R^(c), —C(O)N(R^(b))R^(c), —N(R^(d))C(O)R^(d),         —N(R^(d))SO₂C₁₋₆alkyl, —C(O)C₁₋₆alkyl, —S(O)₀₋₂—C₁₋₆alkyl,         —SO₂N(R^(b))R^(c), halo, —CF₃, —COOH, and —COOC₁₋₆alkyl;         -   where R^(b) and R^(c) are each independently —H or             —C₁₋₆alkyl; and         -   where R^(d) is —H or —C₁₋₆alkyl; -   R³ is —CO₂C₁₋₄alkyl, or an aryl or heteroaryl group unsubstituted or     substituted with one or two R^(e) substituents;     -   where each R^(e) is independently —OH, —OC₁₋₆alkyl, —CN,         —N(R^(f))R^(g), —C(O)N(R^(f))R^(g), —N(R^(h))C(O)R^(h),         —N(R^(h))SO₂C₁₋₆alkyl, —C(O)C₁₋₆alkyl, —S(O)₀₋₂—C₁₋₆alkyl,         —SO₂N(R^(f))R^(g), halo, —CF₃, —COOH, and —COOC₁₋₆alkyl;         -   where R^(f) and R^(g) are each independently —H or             —C₁₋₆alkyl; and         -   where R^(h) is —H or —C₁₋₆alkyl; -   R⁴ is an aryl or heteroaryl group unsubstituted or substituted with     one or two R^(i) substituents;     -   where each R^(i) is independently —OH, —OC₁₋₆alkyl, —CN,         —N(R^(j))R^(k), —C(O)N(R^(j))R^(k), —N(R^(l))C(O)R^(l),         —N(R^(l))SO₂C₁₋₆alkyl, —C(O)C₁₋₆alkyl, —S(O)₀₋₂—C₁₋₆alkyl,         —SO₂N(R^(j))R^(k), halo, —CF₃, —COOH, and —COOC₁₋₆alkyl;         -   where R^(j) and R^(k) are each independently —H or             —C₁₋₆alkyl; and         -   where R^(l) is —H or —C₁₋₆alkyl; -   R⁵ is H or methyl; or R⁴ and R⁵ together form —(CH₂)₄—; and -   the base is selected from the group consisting of potassium     tert-butoxide, sodium tert-butoxide, lithium tert-butoxide,     potassium isopropoxide, sodium isopropoxide, lithium isopropoxide,     potassium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide,     lithium bis(trimethylsilyl)amide, and isopropylmagnesium chloride.

An object of the present invention is to overcome or ameliorate at least one of the disadvantages of the conventional methodologies and/or prior art, or to provide a useful alternative thereto.

Additional embodiments, features, and advantages of the invention will be apparent from the following detailed description and through practice of the invention.

DETAILED DESCRIPTION

The invention may be more fully appreciated by reference to the following description, including the following glossary of terms and the concluding examples. For the sake of brevity, the disclosures of the publications, including patents, cited in this specification are herein incorporated by reference.

As used herein, the terms “including”, “containing” and “comprising” are used herein in their open, non-limiting sense.

The term “alkyl” refers to a straight- or branched-chain alkyl group having from 1 to 12 carbon atoms in the chain. Examples of alkyl groups include methyl (Me, which also may be structurally depicted by a bond “/”), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples.

“Aryl”, also “Ar” or “aryl”, includes phenyl, also “Ph”, and naphthyl.

The term “heteroaryl” refers to a monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (ring structure having ring atoms selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms per heterocycle. Illustrative examples of heteroaryl groups include the following entities, in the form of properly bonded moieties:

Those skilled in the art will recognize that the species of alkyl, aryl, and heteroaryl groups listed or illustrated above are not exhaustive, and that additional species within the scope of these defined terms may also be selected.

The term “halogen” represents chlorine, fluorine, bromine or iodine. The term “halo” represents chloro, fluoro, bromo or iodo.

The term “polar, aprotic organic solvent” refers to a solvent with a high dielectric constant (e.g. above 7.5), but which lacks hydroxyl groups or similar hydrogen-bond donating functionalities (Carey, F. A. and R. J. Sundberg, “Advanced Organic Chemistry,” 3^(rd) ed., 1990, Part B, p. 21). Examples of polar, aprotic organic solvents include, but are not limited to, tetrahydrofuran, N,N-dimethylformamide, acetone, N,N-dimethylsulfoxide, N,N-dimethylacetamide, and acetonitrile.

The term “strong acid” as used herein represents a protic acid of a pH below about 4, including, but not limited to, TFA, methanesulfonic acid, benzenesulfonic acid, and para-toluenesulfonic acid (TsOH).

The ring positions of pyrazoles described herein, such as compounds of Formula (I), are numbered as follows:

The term “substituted” means that the specified group or moiety bears one or more substituents. The term “unsubstituted” means that the specified group bears no substituents. The term “optionally substituted” means that the specified group is unsubstituted or substituted by one or more substituents. Where the term “substituted” is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system. In cases where a specified moiety or group is not expressly noted as being optionally substituted or substituted with any specified substituent, it is understood that such a moiety or group is intended to be unsubstituted.

Any formula given herein is intended to represent compounds having structures depicted by the structural formula as well as certain variations or forms. In particular, compounds of any formula given herein may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of the compounds of the general formula, and mixtures thereof, are considered within the scope of the formula. Thus, any formula given herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof. Furthermore, certain structures may exist as geometric isomers (i.e., cis and trans isomers), as tautomers, or as atropisomers. Additionally, any formula given herein is intended to embrace hydrates, solvates, and polymorphs of such compounds, and mixtures thereof. Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²⁵I, respectively.

When referring to any formula given herein, the selection of a particular moiety from a list of possible species for a specified variable is not intended to define the moiety for the variable appearing elsewhere. In other words, where a variable appears more than once, the choice of the species from a specified list is independent of the choice of the species for the same variable elsewhere in the formula.

In preferred embodiments of Formula (I), R¹ is phenyl, 4-cyanophenyl, 4-methoxyphenyl, 3,5-dichlorophenyl, naphthyl, or methyl.

In preferred embodiments, R³ is phenyl, 4-chlorophenyl, 4-methoxycarbonylphenyl, 4-nitrophenyl, 3-cyanophenyl, 4-methoxyphenyl, 4-dimethylaminophenyl, or ethoxycarbonyl.

In preferred embodiments, R⁴ is phenyl, benzo[1,3]dioxolyl, 2-chloro-6-fluorophenyl, 4-bromophenyl, 3-trifluoromethylphenyl, 4-nitrophenyl, 2-thienyl, 2-furanyl, or 3-pyridyl.

In preferred embodiments, R⁵ is H.

In preferred embodiments, the strong base is KOtBu.

In preferred embodiments, the solvent is THF.

In preferred embodiments, the strong acid is TFA, methanesulfonic acid, benzenesulfonic acid, or para-toluenesulfonic acid. In further preferred embodiments, the strong acid is TFA.

A “salt” is intended to mean a salt of a free acid or base of a compound represented by Formula (I). A compound of Formula (I) may possess a sufficiently acidic group, a sufficiently basic group, or both types of functional groups, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. Examples of salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.

If the compound of Formula (I) contains a basic nitrogen, the desired salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as mandelic acid, citric acid, or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, a sulfonic acid, such as laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, any compatible mixture of acids such as those given as examples herein, and any other acid and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology.

If the compound of Formula (I) is an acid, such as a carboxylic acid or sulfonic acid, the desired salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide, alkaline earth metal hydroxide, any compatible mixture of bases such as those given as examples herein, and any other base and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology. Illustrative examples of suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, carbonates, bicarbonates, primary, secondary, and tertiary amines, and cyclic amines, such as benzylamines, pyrrolidines, piperidine, morpholine, and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

In the context of this invention, it seemed that a deprotonated hydrazone might possess a reversed nucleophilicity toward a Michael receptor such as a nitroolefin. Indeed, when potassium tert-butoxide (KOtBu or KOBu^(t)) was added to hydrazone 1 in tetrahydrofuran (THF) at 0° C. under N₂ followed by the addition of nitroolefin 2, 1,3,4-trisubstituted pyrazole 4 was isolated in 45% yield after 30 minutes at 0° C. (Scheme 2, reaction B). Although the yield was rather low, no 1,3,5-trisubstituted pyrazole 3 was observed. Notably, the base-mediated reaction B does not require air, which is essential for reaction A to proceed. Actually, when reaction B was performed in the presence of air, oxidative dimerization of the hydrazone itself was the dominant reaction (Buckingham, J. Q. Rev. Chem. Soc. 1969, 23, 37-56).

In attempts to optimize reaction B, altering the solvent (CH₃CN, CH₂Cl₂, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA)), reaction temperature (−78° C.), or strong base (NaOBu^(t), LiOBu^(t), sodium bis(trimethylsilyl)amide (NaHMDS), LiHMDS, and ^(i)PrMgCl) all provided the desired pyrazole 4, most with comparable success to the KOBu^(t)/THF conditions. Using PhMgCl or lithium diisopropylamide (LDA) as the strong base afforded only trace amounts of product. Changing the order of addition of the reagents, by adding KOBu^(t) to the solution of hydrazone 1 and nitroolefin 2 in THF, did not significantly affect the outcome.

Studies in the context of this invention revealed the outcome of the reaction depended on the quenching method used (Scheme 3). In these parallel experiments, KOBu^(t) was added to −78° C. solutions of hydrazone 5 in THF under N₂, followed by the addition of nitroolefin 6 after 10 minutes. After stirring at −78° C. for a further 10 minutes, both hydrazone 5 and nitroolefin 6 were completely consumed based on HPLC analysis. Two equivalents of a quenching reagent selected from H₂O, MeOH, acetic acid (AcOH), benzenesulfonic acid, CH₃SO₃H, and TFA were then added to each reaction vessel. After further stirring at −78° C. for 2 hours, the reaction solutions were warmed to room temperature slowly overnight. The results are depicted in Scheme 3. When no quenching reagents or water were used, starting materials were mostly recovered. MeOH (pKa=15.5) quenching caused a very messy reaction. Besides the desired pyrazole 7 obtained in 12% yield, the only other isolable product was 5-aminopyrazole 8 in 18% yield, which perhaps arose from an internal Redox reaction. With AcOH (pKa=4.7) as the quenching reagent, desired pyrazole 7 was not observed. Instead, the major product was Michael addition product 9, isolated in 40% yield. Finally, when TFA (pKa=−0.25) was used as the quenching reagent, a clean transformation was achieved to afford desired pyrazole 7 in 77% isolated yield. Comparable isolated yields were also obtained with PhSO₃H (pKa=2.1) and CH₃SO₃H (pKa=−2.6) as the quenching reagents. It is important to note that when isolated compound 9 was subjected to the KOBu^(t)/TFA sequence, pyrazole 7 was obtained almost quantitatively, which suggests the intermediacy of compound 9 in the pyrazole forming reaction.

Without being bound by a particular hypothesis, a possible mechanism for the pyrazole formation reaction is shown in Scheme 4. Michael addition of deprotonated hydrazone 10 to a nitroolefin affords intermediate 11 ((a) Fernandez, R. et al. Tetrahedron Lett. 1994, 35, 471-472; (b) Enders, D. et al. Synthesis 1996, 48-52). An intramolecular addition then furnishes cyclized intermediate 12. An oxidative aromatization then generates the desired pyrazole product. Since the reaction is performed under N₂ without an external oxidant, the byproduct HNO₂ likely serves as an internal oxidant.

In this process, it is not clear whether intermediate 10 or 11 is the resting stage. Low temperature nuclear magnetic resonance (NMR) experiments (−25° C.) showed the disappearance of the starting materials in several minutes but failed to provide a clean spectrum of the proposed intermediate. Nevertheless, these first two steps are most likely reversible due to the fact that the starting materials are recovered when no quenching or water quenching is used. The role of a strong acid quenching agent in these reactions is not entirely clear. One possible explanation is that the elimination of NO₂ ⁻ under basic conditions is a slow process, which allows other decomposition pathways to occur, resulting in the low yields observed with unquenched reactions. Conversely, strong acid protonation of intermediate 12 would afford intermediate 13, which perhaps allows a faster elimination of HNO₂, thus suppressing the other competing pathways.

With optimized conditions in hand and a reasonable understanding of the reaction mechanism, the scope of this reaction was examined (Table 1). A diverse set of representative nitroolefins was reacted with hydrazone 1 under the standard KOBu^(t)/TFA conditions without individual optimization. At the R⁴ position, both electron-donating and electron-withdrawing groups, with various aromatic substitution patterns, are compatible with the reaction conditions (entries 1-5). Notably, a sterically hindered ortho-disubstituted nitroolefin worked efficiently (entry 2). Substitutions at the R⁵ position were well tolerated (entries 6 and 7). Nitroolefins with aliphatic (entry 7) or heteroaryl groups such as thiophene, furan and pyridine (entries 8-10) at the R⁴ position afforded good yields of pyrazoles as well.

TABLE 1 Reaction Scope with Respect to the Nitroolefin

entry nitro-olefin product yield 1

79% 2

88% 3

81% 4

76% 5

52% 6

82% 7

63% 8

73% 9

51% 10

42%

The scope of the reaction with respect to the hydrazone reagent was examined (Table 2). High yields were achieved when R³ was a phenyl ring substituted with electron-withdrawing groups (Table 2, entries 1-3). With electron-donating substituents on the R³ phenyl ring, products were observed, albeit in lower yield (entries 4-5). Without being bound by hypothesis, an electron-withdrawing group may help stabilize deprotonated hydrazone 10 (Scheme 4), thus facilitating the Michael addition step. Non-aromatic R³ groups were also well tolerated, as pyrazole 32, the regioisomer of the key intermediate for rimonbant, was prepared in high yield (entry 10).

Substitution at the R¹ position was then investigated. Here the electronic effect was also prominent. However, the effect was observed in a reversed fashion: an electron-withdrawing substituent on an R¹ phenyl ring afforded a very poor yield (entry 6), whereas an electron-donating substituent facilitated the reaction (entry 7). Without being bound by hypothesis, the electronic properties of the R¹ group may have less of an effect on the first Michael addition step because the R¹ group is far away from the reaction site. Meanwhile, on the subsequent addition step, an electron-withdrawing R¹ group would significantly increase the electron-density on the adjacent nitrogen atom in intermediate 11, thus impeding the formation of intermediate 12. However, for pyridyl substituents at the R¹ position gave different results (entry 9). When no quenching was employed, desired pyrazole 31 was isolated in a low 16% yield (entry 9b). In contrast, with the strong acid quenching method, open-chain nitroso compound 30 was obtained in 81% yield (entry 9a), presumably through the dehydration of protonated intermediate 11. An electron-donating methyl group at the R¹ position was also compatible with the reaction conditions (entry 11). The relatively low yield was likely attributable to the instability of methylhydrazone itself. Compared with electronic properties, the steric properties of the R¹ substituent are less significant. A bulky naphthyl hydrazone furnished pyrazole 29 in 67% yield (entry 8).

TABLE 2 Reaction Scope with Respect to the Hydrazone

entry hydrazone product yield  1

77%  2

80%  3

83%  4

25%  5

31%  6

11%  7

83%  8

67%  9a

81%  9b^(a)

16% 10^(b)

78% 11

41% ^(a)This reaction was not quenched with TFA. ^(b)1-Chloro-4-(2-nitro-propenyl)-benzene was used in this reaction.

Compounds prepared according to the schemes described above may be isolated using conventional separation methods known to one skilled in the art, such as chromatography, crystallization, or salt formation.

Compounds of Formula (I) may be converted to their corresponding salts using methods known to those skilled in the art. For example, amines of Formula (I) may be treated with trifluoroacetic acid (TFA), HCl, maleic acid, or citric acid in a solvent such as diethyl ether (Et₂O), DCM, tetrahydrofuran (THF), or methanol (MeOH) to provide the corresponding salt forms.

Artisans will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. Unless otherwise specified, the variables are as defined above in reference to Formula (I).

In conclusion, a regioselective synthesis of 1,3,4-trisubstituted or 1,3,4,5-tetrasubstituted pyrazoles from hydrazones and nitroolefins was developed. Under basic conditions, an unusual 1,3,4-regioselectivity pattern was obtained exclusively. A Michael addition product was postulated as a key intermediate and a plausible reaction mechanism was proposed. This reaction is quite broad in scope, generating a diverse set of pyrazole products in moderate to excellent yields. Partnered with the 1,3,5-trisubstituted pyrazole synthesis previously developed (Deng, X.; Mani, N. S. 2006), the reaction of hydrazones and nitroolefins provides a general method to access pyrazoles with different substitution patterns.

The following examples are provided to further illustrate the invention and various preferred embodiments.

EXAMPLES Chemistry:

In preparing the compounds described in the examples below and obtaining the corresponding analytical data, the following experimental and analytical protocols were followed unless otherwise indicated.

Unless otherwise specified, reaction mixtures were magnetically stirred at room temperature (rt) under a N_(2(g)) atmosphere. Where solutions were “dried,” they were generally dried over a drying agent such as Na₂SO₄ or MgSO₄. Where mixtures, solutions, and extracts were “concentrated”, they were typically concentrated on a rotary evaporator under reduced pressure.

The reaction flasks were flame-dried prior to use. THF was dried over alumina. All the hydrazones were prepared according from the corresponding aldehydes and hydrazines using methods known in the art. All the nitroolefins were purchased from commercial sources and used without further purification.

Normal phase flash column chromatography (FCC) was typically performed with Merck silica gel 60, unless otherwise indicated.

HPLC analysis was performed on a Hewlett Packard 1100, using an Agilent ZORBAX® Eclipse XDB-C8, 5 μm, 4.6×150 mm column, a flow rate of 1 mL/min, and a gradient (acetonitrile/water with 0.05% trifluoroacetic acid) of 1% acetonitrile/99% water to 99% acetonitrile/1% water ramp over 8 min.

Nuclear magnetic resonance (NMR) spectra were obtained on Bruker model DRX spectrometers. The format of the ¹H NMR data below is: chemical shift in ppm downfield of the tetramethylsilane reference (multiplicity, coupling constant J in Hz, integration). Multiplicity is given as s (singlet), d (doublet), t (triplet), q (quartet), or m (multiplet). One-dimension Nuclear Overhauser Effect (NOE) experiments were performed at Bruker 500 NMR spectrometer by the method of Stott, et al. with a mixing time of 0.8 sec (Stott, K.; Keeler, J.; Van, Q. N.; Shaka, A. J. J. Magn. Reson., 1997, 125, 302-324).

Infrared spectroscopy was performed on a Nicolet Avatar 360 FT-IR.

High resolution mass spectrometry (HRMS) was performed using electrospray ionization (ESI) on a Bruker μTof.

Chemical names were generated using ChemDraw Ultra 6.0.2 (CambridgeSoft Corp., Cambridge, Mass.).

Example 1 4-(1-Phenyl-4-p-tolyl-1H-pyrazol-3-yl)-benzoic acid methyl ester

To a −78° C. solution of 4-(phenyl-hydrazonomethyl)-benzoic acid methyl ester (127 mg, 0.50 mmol, 1.0 equiv.) in THF (5 mL) was added KOBu^(t) (1.0 mol/L in THF, 0.5 mL, 0.5 mmol, 1.0 equiv.) was added dropwise. After stirring at −78° C. for 10 min, trans-4-methyl-ω-nitrostyrene (82 mg, 0.5 mmol, 1.0 equiv.) in THF (2 mL) was added dropwise via syringe. After 15 min, TFA (77 uL, 1.0 mmol, 2.0 equiv) was added via syringe. The reaction solution was stirred at −78° C. for ca. 2 h and then allowed to warm to room temperature (rt) overnight. The solution was diluted with EtOAc (30 mL) and water (30 mL). The organic layer was separated, dried, and concentrated. The crude product was purified by FCC (EtOAc/hexanes) to afford the title compound in 77% yield (142 mg, 0.39 mmol). HPLC: R_(T)=11.78 min. TLC (EtOAc/Hexanes=1:4): R_(f)=0.35. ¹H NMR (500 MHz, CDCl₃, δ): 8.02-7.98 (m, 2H), 7.98 (s, 1H), 7.82-7.77 (m, 2H), 7.69 (dt, J=8.5, 1.8 Hz, 2H), 7.52-7.44 (m, 2H), 7.36-7.28 (m, 2H), 7.22 (dt, J=8.1, 1.6 Hz, 2H), 7.18-7.13 (m, 2H), 3.91 (s, 3H), 2.38 (s, 3H). ¹³C NMR (125.7 MHz, CDCl₃, δ): 167.0, 149.2, 139.8, 137.8, 137.0, 129.6, 129.5, 129.3, 129.2, 128.6, 128.1, 126.8, 126.6, 123.4, 119.0, 52.0, 21.1. HRMS-ESI (m/z): [M+H]⁺ calcd for C₂₄H₂₁N₂O₂ 369.1598; found, 369.1592.

The compounds in Examples 2-24 were prepared using methods analogous to those described in Example 1, with exceptions where noted. Yields are provided in Tables 1 and 2.

Example 2 4-Benzo[1,3]dioxol-5-yl-3-(4-chloro-phenyl)-1-phenyl-1H-pyrazole.

HPLC: R_(T)=11.65 min. TLC (EtOAc/Hexanes=1:4): R_(f)=0.33. ¹H NMR (500 MHz, CDCl₃, δ): 7.93 (s, 1H), 7.78-7.72 (m, 2H), 7.54 (td, J=8.6, 1.9 Hz, 2H), 7.50-7.42 (m, 2H), 7.34-7.27 (m, 3H), 6.81-6.79 (m, 2H), 6.79-6.76 (m, 1H), 5.98 (s, 2H). ¹³C NMR (125.7 MHz, CDCl₃, δ): 149.13, 147.79, 146.86, 139.80, 133.79, 131.53, 129.58, 129.47, 128.54, 126.70, 126.57, 126.31, 122.68, 122.21, 118.92, 109.30, 108.54, 101.11. IR (dry film, cm⁻¹): 2907.1 (w), 1599.1 (m), 1502.1 (s), 1484.6 (s), 1439.5 (s), 1216.4 (s). HRMS-ESI (m/z): [M+H]⁺ calcd for C₂₂H₁₆ClN₂O₂ 375.0900; found, 375.0894.

Example 3 4-(2-Chloro-6-fluoro-phenyl)-3-(4-chloro-phenyl)-1-phenyl-1H-pyrazole

HPLC: R_(T)=11.77 min. TLC (EtOAc/Hexanes=1:4): R_(f)=0.48. ¹H NMR (500 MHz, CDCl₃, δ): 8.01 (s, 1H), 7.79 (dt, J=8.2, 1.6 Hz, 2H), 7.52-7.44 (m, 4H), 7.34-7.22 (m, 5H), 7.08-7.02 (m, 1H). ¹³C NMR (125.7 MHz, CDCl₃, δ): 171.1, 160.8 (d, J_(C-F)=249 Hz), 150.4, 139.8, 135.8, 133.9, 131.9, 129.8 (d, J_(C-F)=9.5 Hz), 129.5, 128.6, 128.1, 126.8, 125.5 (d, J_(C-F)=3.6 Hz), 120.8 (d, J_(C-F)=19.1 Hz), 119.1, 114.3 (d, J_(C-F)=22.9 Hz), 112.2. HRMS-ESI (m/z): [M+H]⁺ calcd for C₂₁H₁₄N₂FCl₂, 383.0513; found, 383.0519.

Example 4 4-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-1-phenyl-1H-pyrazole

HPLC: R_(T)=12.75 min. TLC (EtOAc/Hexanes=1:4): R_(f)=0.47. ¹H NMR (500 MHz, CDCl₃, δ): 7.98 (s, 1H), 7.85-7.74 (m, 2H), 7.62-7.44 (m, 6H), 7.40-7.28 (m, 3H), 7.26-7.16 (m, 2H). ¹³C NMR (125.7 MHz, CDCl₃, δ): 149.2, 139.7, 134.1, 131.8, 131.6, 131.3, 130.2, 129.7, 129.5, 128.7, 126.8, 126.7, 121.8, 121.2, 119.0. HRMS-ESI (m/z): [M+H]⁺ calcd for C₂₁ H₁₅N₂ClBr, 409.0102; found, 409.0103.

Example 5 3-(4-Chloro-phenyl)-1-phenyl-4-(3-trifluoromethyl-phenyl)-1H-pyrazole

HPLC: R_(T)=12.21 min. TLC (EtOAc/Hexanes=1:4): R_(f)=0.40. ¹H NMR (500 MHz, CDCl₃, δ): 8.03 (s, 1H), 7.84-7.76 (m, 2H), 7.63 (s, 1H), 7.60-7.40 (m, 7H), 7.38-7.26 (m, 3H). ¹³C NMR (125.7 MHz, CDCl₃, δ): 149.3, 139.7, 134.2, 133.5, 132.0, 131.2, 131.1 (q, J_(C-F)=32.0 Hz), 129.7, 129.6, 129.1, 128.7, 127.1, 126.9, 125.2 (q, J_(C-F)=3.5 Hz), 123.8 (q, J_(C-F)=3.7 Hz), 124.0 (d, J_(C-F)=272 Hz), 121.5, 119.1. HRMS-ESI (m/z): [M+H]⁺ calcd for C₂₂H₁₅N₂F₃Cl, 399.0870; found, 399.0886.

Example 6 3-(4-Chloro-phenyl)-4-(4-nitro-phenyl)-1-phenyl-1H-pyrazole

HPLC: R_(T)=11.02 min. TLC (EtOAc/Hexanes=1:4): R_(f)=0.23. ¹H NMR (500 MHz, CDCl₃, δ): 8.20 (dt, J=8.8, 1.9 Hz, 2H), 8.12 (s, 1H), 7.82-7.76 (m, 2H), 7.57-7.45 (m, 6H), 7.41-7.34 (m, 3H). ¹³C NMR (125.7 MHz, CDCl₃, δ): 149.7, 146.75, 139.6, 139.5, 134.6, 130.9, 129.9, 129.6, 128.9, 127.3, 127.2, 124.1, 120.9, 119.2. HRMS-ESI (m/z): [M+H]⁺ calcd for C₂₁H₁₅N₃O₂Cl, 376.0847; found, 376.0849.

Example 7 3-(4-Chloro-phenyl)-5-methyl-1,4-diphenyl-1H-pyrazole

HPLC: R_(T)=11.84 min. TLC (EtOAc/Hexanes=1:4): R_(f)=0.39. ¹H NMR (500 MHz, CDCl₃, δ): 7.60-7.55 (m, 2H), 7.51 (dt, J=7.5, 2.1 Hz, 2H), 7.46-7.36 (m, 5H), 7.32 (tt, J=7.3, 2.4 Hz, 2H), 7.28-7.24 (m, 2H), 7.22 (dt, J=8.7, 2.0 Hz, 2H), 2.30 (s, 3H). ¹³C NMR (125.7 MHz, CDCl₃, δ): 148.5, 139.9, 137.9, 133.6, 133.3, 131.9, 130.2, 129.3, 129.2, 128.6, 128.3, 127.9, 127.0, 125.1, 120.2, 11.6. HRMS-ESI (m/z): [M+H]⁺ calcd for C₂₂H₁₈N₂Cl, 345.1153; found, 345.1155.

Example 8 3-(4-Chloro-phenyl)-1-phenyl-4,5,6,7-tetrahydro-1H-indazole

The analytical data obtained were identical with the literature data.

Example 9 3-(4-Chloro-phenyl)-1-phenyl-4-thiophen-2-yl-1H-pyrazole

HPLC: R_(T)=11.90 min. TLC (EtOAc/Hexanes=1:4): R_(f)=0.46. ¹H NMR (500 MHz, CDCl₃, δ): 8.02 (s, 1H), 7.78-7.72 (m, 2H), 7.60 (dt, J=8.5, 1.8 Hz, 2H), 7.49-7.42 (m, 2H), 7.36-7.22 (m, 4H), 7.00 (dd, J=5.2, 3.5 Hz, 1H), 6.93 (dd, J=3.5, 1.1 Hz, 1H). ¹³C NMR (125.7 MHz, CDCl₃, δ): 149.4, 139.5, 134.1, 133.6, 131.2, 129.7, 129.4, 128.5, 127.5, 127.1, 126.7, 126.0, 124.9, 118.9, 115.8. HRMS-ESI (m/z): [M+H]⁺ calcd for C₁₉H₁₄N₂SCl, 337.0561; found, 337.0568.

Example 10 3-(4-Chloro-phenyl)-4-furan-2-yl-1-phenyl-1H-pyrazole

HPLC: R_(T)=11.6 min. TLC (EtOAc/Hexanes=1:4): R_(f)=0.41. ¹H NMR (500 MHz, CDCl₃, δ): 8.15 (s, 1H), 7.75 (dt, J=8.5, 2.0 Hz, 2H), 7.64 (dt, J=8.5, 1.9 Hz, 2H), 7.50-7.42 (m, 2H), 7.42, 7.36 (m, 3H), 7.33-7.27 (m, 1H), 6.39 (dd, J=3.3, 1.8 Hz, 1H), 6.24 (d, J=3.2 Hz, 1H). ¹³C NMR (125.7 MHz, CDCl₃, δ): 149.0, 146.9, 141.4, 139.6, 134.3, 131.6, 129.8, 129.5, 128.6, 126.8, 126.1, 119.0, 113.7, 111.2, 106.7. HRMS-ESI (m/z): [M+H]⁺ calcd for C₁₉H₁₄N₂OCl, 321.0789; found, 321.0798.

Example 11 3-[3-(4-Chloro-phenyl)-1-phenyl-1H-pyrazol-4-yl]-pyridine

The compound decomposed slowly during purification. HPLC: R_(T)=8.58 min. ¹H NMR (500 MHz, CD₃OD, δ): 8.60 (s, 1H), 8.60-8.45 (m, 2H), 7.94-7.88 (m, 2H), 7.84-7.78 (m, 1H), 7.58-7.48 (m, 4H), 7.48-7.35 (m, 4H). ¹³C NMR (125.7 MHz, CD₃OD, δ): 150.9, 149.6, 148.5, 141.1, 138.1, 135.5, 132.8, 131.2, 130.7, 129.9, 129.6, 128.2, 120.3, 120.2. HRMS-ESI (m/z): [M+H]⁺ calcd for C₂₀H₁₅ClN₃ 332.0949; found, 332.0949.

Example 12 3-(4-Nitro-phenyl)-1-phenyl-4-p-tolyl-1H-pyrazole

HPLC: R_(T)=11.71 min. TLC (EtOAc/Hexanes=1:4): R_(f)=0.34. ¹H NMR (500 MHz, CDCl₃, δ): 8.15 (dt, J=8.9, 2.0 Hz, 2H), 7.99 (s, 1H), 7.82-7.77 (m, 4H), 7.52-7.46 (m, 2H), 7.33 (td, J=7.4, 1.0 Hz, 1H), 7.24-7.16 (m, 4H), 2.39 (s, 3H). ¹³C NMR (125.7 MHz, CDCl₃, δ): 147.7, 147.1, 139.8, 139.6, 137.3, 129.5, 129.5, 129.0, 128.7, 128.6, 127.2, 126.9, 123.7, 123.5, 119.0, 21.1. HRMS-ESI (m/z): [M+H]⁺ calcd for C₂₂H₁₈N₃O₂ 356.1394; found, 356.1393.

Example 13 3-(1-Phenyl-4-p-tolyl-1H-pyrazol-3-yl)-benzonitrile

HPLC: R_(T)=1.38 min. TLC (EtOAc/Hexanes=1:4): R_(f)=0.31. ¹H NMR (500 MHz, CDCl₃, δ): 7.97 (s, 1H), 7.96 (t, J=1.3 Hz, 1H), 7.80 (dt, J=7.9, 1.3 Hz, 1H), 7.79-7.75 (m, 2H), 7.57 (dt, J=7.7, 1.3 Hz, 1H), 7.52-7.45 (m, 2H), 7.39 (t, J=7.8 Hz, 1H), 7.32 (tt, J=7.4, 1.0 Hz, 1H), 7.23-7.14 (m, 4H), 2.38 (s, 3H). ¹³C NMR (125.7 MHz, CDCl₃, δ): 147.8, 139.6, 137.2, 134.6, 132.4, 131.6, 131.1, 129.4, 129.4, 128.9, 128.5, 126.9, 126.7, 123.1, 118.9, 118.7, 112.4, 21.1. HRMS-ESI (m/z): [M+H]⁺ calcd for C₂₃H₁₈N₃ 336.1495; found, 336.1497.

Example 14 3-(4-Methoxy-phenyl)-1-phenyl-4-p-tolyl-1H-pyrazole

HPLC: R_(T)=11.52 min. TLC (EtOAc/Hexanes=1:4): R_(f)=0.33. ¹H NMR (400 MHz, CDCl₃, δ): 7.96 (s, 1H), 7.81-7.75 (m, 2H), 7.54 (dt, J=8.9, 2.1 Hz, 2H), 7.50-7.42 (m, 2H), 7.32-7.21 (m, 3H), 7.18-7.12 (m, 2H), 6.87 (dt, J=8.8, 2.1 Hz, 2H), 3.81 (s, 3H), 2.37 (s, 3H). ¹³C NMR (100 MHz, CDCl₃, δ): 159.3, 150.1, 139.9, 136.5, 129.9, 129.6, 129.3, 129.2, 128.5, 126.3, 126.1, 125.7, 122.5, 118.8, 113.7, 55.2, 21.1. HRMS-ESI (m/z): [M+H]⁺ calcd for C₂₃H₂₁N₂O 341.1648; found, 341.1642.

Example 15 Dimethyl-[4-(1-phenyl-4-p-tolyl-1H-pyrazol-3-yl)-phenyl]-amine

HPLC: R_(T)=9.69 min. TLC (EtOAc/Hexanes=1:4): R_(f)=0.35. ¹H NMR (500 MHz, CDCl₃, δ): 7.94 (s, 1H), 7.81-7.75 (m, 2H), 7.60-7.40 (m, 4H), 7.32-7.22 (m, 3H), 7.18-7.12 (m, 2H), 6.73-6.67 (m, 2H), 2.96 (s, 6H), 2.37 (s, 3H). ¹³C NMR (125.7 MHz, CDCl₃, δ): 150.7, 150.0, 140.1, 136.3, 130.4, 129.3, 129.1, 129.1, 128.6, 126.3, 125.9, 122.3, 121.5, 118.7, 112.2, 40.5, 21.1. HRMS-ESI (m/z): [M+H]⁺ calcd for C₂₄H₂₄N₃ 354.1965; found, 354.1973.

Example 16 3-(4-Chloro-phenyl)-1-(4-methoxy-phenyl)-4-p-tolyl-1H-pyrazole

HPLC: R_(T)=12.31 min. TLC (EtOAc/Hexanes=1:4): R_(f)=0.33. ¹H NMR (500 MHz, CDCl₃, δ): 7.87 (s, 1H), 7.66 (dt, J=8.9, 1.9 Hz, 2H), 7.53 (dt, J=8.4, 2.3 Hz, 2H), 7.32-7.27 (m, 2H), 7.21 (d, J=7.9 Hz, 2H), 7.15 (d, J=7.9 Hz, 2H), 6.98 (dt, J=8.9, 1.9, 2H), 3.84 (s, 3H), 2.37 (s, 3H). ¹³C NMR (125.7 MHz, CDCl₃, δ): 158.3, 148.7, 136.7, 133.6, 133.5, 131.8, 129.6, 129.5, 129.3, 128.5, 128.4, 126.8, 122.4, 120.6, 114.5, 55.5, 21.1. HRMS-ESI (m/z): [M+H]⁺ calcd for C₂₃H₂₀ClN₂O 375.1259; found, 375.1255.

Example 17 3-(4-Chloro-phenyl)-1-naphthalen-1-yl-4-p-tolyl-1H-pyrazole

HPLC: R_(T)=12.69 min. TLC (EtOAc/Hexanes=1:4): R_(f)=0.43. ¹H NMR (500 MHz, CDCl₃, δ): 8.08-8.02 (m, 1H), 7.96-7.88 (m, 2H), 7.84 (s, 1H), 7.64 (dd, J=7.3, 1.1 Hz, 1H), 7.59 (dt, J=8.6, 1.9 Hz, 2H), 7.57-7.52 (m, 3H), 7.33-7.26 (m, 4H), 7.17 (d, J=7.8 Hz, 2H), 2.38 (s, 3H). ¹³C NMR (125.7 MHz, CDCl₃, δ): 148.9, 137.0, 136.8, 134.4, 133.6, 131.82, 131.77, 129.72, 129.66, 129.4, 129.0, 128.9, 128.6, 128.5, 128.2, 127.3, 126.7, 125.1, 123.3, 123.1, 121.8, 21.2. HRMS-ESI (m/z): [M+H]⁺ calcd for C₂₆H₂₀ClN₂ 395.1310; found, 395.1303.

Example 18 4-[3-(4-Chloro-phenyl)-4-p-tolyl-pyrazol-1-yl]-benzonitrile

HPLC: R_(T)=12.08 min. TLC (EtOAc/Hexanes=1:4): R_(f)=0.25. ¹H NMR (400 MHz, CDCl₃, δ): 8.03 (s, 1H), 7.91 (dt, J=8.9, 2.0 Hz, 2H), 7.77 (dt, J=8.9, 2.0 Hz, 2H), 7.53 (dt, J=8.6, 2.0 Hz, 2H), 7.31 (dt, J=8.6, 2.0 Hz, 2H), 7.24-7.15 (m, 4H), 2.39 (s, 3H). ¹³C NMR (100 MHz, CDCl₃, δ): 150.7, 142.6, 137.5, 134.3, 133.7, 131.0, 129.6, 129.5, 128.8, 128.64, 128.60, 126.46, 124.45, 118.6, 118.4, 109.6, 21.2. HRMS-ESI (m/z): [M+H]⁺ calcd for C₂₃H₁₇ClN₃ 370.1106; found, 370.1098.

Example 19 2-[3-(4-Chloro-phenyl)-4-p-tolyl-pyrazol-1-yl]-pyridine

The solution of a mixture of N-(4-chloro-benzylidene)-N′-pyridin-2-yl-hydrazine (116 mg, 0.5 mmol, 1.0 equiv.) and trans-4-methyl-ω-nitrostyrene (82 mg, 0.5 mmol, 1.0 equiv.) in 7 mL THF was cooled to −78° C. Under N², KOBu^(t) solution (1.0 mol/L, 0.5 mL, 0.5 mmol, 1.0 equiv.) was added dropwise via syringe. The reaction solution was stirred at −78° C. for ca. 2 hours and then allowed to warm to room temperature overnight. 30 mL EtOAc and 30 mL water were added. The organic layer was separated, dried over MgSO₄ and evaporated. The crude product was purified on column chromatography with EtOAc/hexanes as eluents to afford the title compound in 16% yield. HPLC: R_(T)=12.09 min. TLC (EtOAc/Hexanes=1:4): R_(f)=0.44. ¹H NMR (500 MHz, CDCl₃, δ): 8.63 (s, 1H), 8.43 (d, J=4.1 Hz, 1H), 8.08 (d, J=8.3 Hz, 1H), 7.83 (ddd, J=8.3, 7.5, 1.8 Hz, 1H), 7.55 (dt, J=8.5, 1.9 Hz, 2H0, 7.31 (dt, J=8.5, 1.9 Hz, 2H), 7.25-7.13 (m, 5H), 2.38 (s, 3H). ¹³C NMR (125.7 MHz, CDCl₃, δ): 151.3, 150.2, 148.0, 138.6, 136.9, 134.0, 131.7, 129.7, 129.5, 129.3, 128.6, 128.5, 126.8, 123.1, 121.4, 112.3, 21.2. HRMS-ESI (m/z): [M+H]⁺ calcd for C₂₁H₁₇ClN₃346.1106; found, 346.1107.

Example 20 4-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester

HPLC: R_(T)=11.36 min. TLC (EtOAc/Hexanes=1:4): R_(f)=0.17. ¹H NMR (500 MHz, CDCl₃, δ): 7.57 (d, J=2.0 Hz, 2H), 7.42 (s, 1H), 7.41 (d, J=2.0 Hz, 2H), 7.40-7.36 (m, 2H), 7.32-7.27 (m, 2H), 4.30 (q, J=7.12 Hz, 2H), 2.06 (s, 3H), 1.26 (t, J=7.12 Hz, 3H). ¹³C NMR (125.7 MHz, CDCl₃, δ): 162.14, 141.54, 140.40, 136.60, 135.27, 133.42, 133.24, 131.62, 130.55, 130.51, 130.19, 128.19, 128.10, 122.46, 61.01, 14.18, 10.25. IR (dry film, cm⁻¹): 1728.7 (s), 1489.8 (s), 1435.1 (w), 1180.5 (s), 1153.7 (s). HRMS-ESI (m/z): [M+H]⁺ calcd for C₁₉H₁₆Cl₃N₂O₂ 409.0277; found, 409.0280.

Example 21 1-Methyl-3-(4-nitro-phenyl)-4-p-tolyl-1H-pyrazole

HPLC: R_(T)=10.27 min. TLC (EtOAc/Hexanes=1:4): R_(f)=0.10. ¹H NMR (500 MHz, CDCl₃, δ): 8.14 (dt, J=8.9, 2.0 Hz, 2H), 7.68 (dt, J=8.9, 2.0 Hz, 2H), 7.45 (s, 1H), 7.18-7.11 (m, 4H), 4.00 (s, 3H), 2.38 (s, 3H). ¹³C NMR (125.7 MHz, CDCl₃, δ): 146.9, 146.2, 140.3, 137.0, 130.8, 129.52, 129.47, 128.7, 128.4, 123.6, 122.1, 39.3, 21.2. The relative stereochemistry was confirmed by Noe study. HRMS-ESI (m/z): [M+H]⁺ calcd for C₁₇H₁₆N₃O₂ 294.1237; found, 294.1227.

Example 22 4-(3-Nitro-1-phenylazo-2-p-tolyl-propyl)-benzoic acid methyl ester

Following the general method described above, AcOH instead of TFA was used to quench the reaction. After the same aqueous workup, 5 mL MeOH was added to the crude product and the solution was stirred at room temperature for 30 minutes. The yellow solid precipitated out was collected by filtration and washed with MeOH to afford the pure title compound in 40% yield. HPLC: R_(T)=10.65 min. ¹H NMR (500 MHz, CDCl₃, δ): 8.02 (dt, J=8.4, 1.8 Hz, 2H), 7.62-7.55 (m, 2H), 7.48-7.40 (m, 5H), 7.05 (d, J=7.8 Hz, 2H), 7.02-6.96 (m, 2H), 5.07 (d, J=7.5, 1H), 4.73-4.62 (m, 2H), 4.44 (td, J=8.6, 6.5 Hz, 1H), 3.92 (s, 3H), 2.27 (s, 3H). ¹³C NMR (125.7 MHz, CDCl₃, δ): 166.6, 151.7, 142.5, 137.7, 132.25, 131.22, 130.1, 130.0, 129.4, 129.0, 128.6, 128.4, 122.5, 83.4, 52.22, 49.26, 21.07. A COSY NMR experiment confirmed that assigned structure. HRMS-ESI (m/z): [M+H]⁺ calcd for C₂₄H₂₄N₃O₄ 418.1761; found, 418.1763.

Example 23 4-(5-Amino-1-phenyl-4-p-tolyl-1H-pyrazol-3-yl)-benzoic acid methyl ester

Following the general method described above, MeOH instead of TFA was used to quench the reaction. After the same aqueous workup and purification procedure, in addition to the desired product (ca. 13% yield), the title compound isolated in 18% yield. HPLC: R_(T)=10.15min. TLC (EtOAc/Hexanes=1:4): R_(f)=0.14. ¹H NMR (500 MHz, DMSO-d6, δ): 7.86 (dt, J=8.5, 1.8 Hz, 2H), 7.74-7.70 (m, 2H), 7.58-7.50 (m, 4H), 7.40 (tt, J=7.4, 1.0 Hz, 1H), 7.20 (d, J=7.8 Hz, 2H), 7.11 (d, J=8.0 Hz, 2H), 5.08 (s, 2H), 3.83 (s, 3H), 2.33 (s, 3H). ¹³C NMR (125.7 MHz, DMSO-d6, δ): 165.9, 147.0, 144.7, 138.8, 138.4, 135.4, 129.6, 129.5, 129.3, 129.2, 128.9, 128.2, 127.4, 126.9, 123.4, 103.4, 51.9, 20.7. Noe and COSY experiments were used to confirm the assigned structure. HRMS-ESI (m/z): [M+H]⁺ calcd for C₂₄H₂₂N₃O₂ 384.1707; found, 384.1703.

Example 24 [1-(4-Chloro-phenyl)-3-nitroso-2-p-tolyl-allyl]-pyridin-2-yl-diazene

Following the general method described above, after aqueous workup with EtOAc/water (even brine caused the decomposition of the title compound), the crude product was directly purified on prep. HPLC to afford the title compound in 81% yield. Based on NMR spectra, two inseparable isomers with identical MS existed, presumably from the cis-trans isomers. HPLC: R_(T)=8.71 min. ¹H NMR (500 MHz, DMSO-d6, δ): 12.36 (s, 1H), 8.7 (dt, J=6.6, 1.0 Hz, 1H), 8.43 (ddd, J=8.9, 7.2, 1.3 Hz, 1H), 8.10 (s, 1H), 8.07-7.98 (m, 1H), 7.74 (dt, J=8.6, 1.8 Hz, 2H), 7.59 (d, J=8.2 Hz, 2H), 7.53 (dt, J=8.5, 1.7 Hz, 2H), 7.39 (td, J=7.1, 1.0 Hz, 1H), 7.21 (d, J=8.0 Hz, 2H), 6.85 (s, 1H), 2.28 (s, 3H). ¹³C NMR (125.7 MHz, DMSO-d6, δ): 152.1, 148.5, 147.2, 147.0, 139.6, 136.2, 131.9, 130.0, 129.8, 129.66, 129.59, 129.0, 127.6, 117.8, 111.1, 61.5, 21.2. HRMS-ESI (m/z): [M+H]⁺ calcd for C₂₁H₁₈ClN₄O 377.1164; found, 377.1167. 

1. A process for the preparation of compounds of Formula (I) and salts thereof:

comprising (a) reacting a hydrazone of formula (II):

with a nitroolefin of formula (III):

in the presence of a strong base of formula (XI):

in a polar, aprotic organic solvent; and (b) quenching the reaction with a strong acid; wherein R¹ is C₁₋₆alkyl, or an aryl group unsubstituted or substituted with one or two R^(a) substituents; where each R^(a) is independently —OH, —OC₁₋₆alkyl, —CN, —N(R^(b))R^(c), —C(O)N(R^(b))R^(c), —N(R^(d))C(O)R^(d), —N(R^(d))SO₂C₁₋₆alkyl, —C(O)C₁₋₆alkyl, —S(O)₀₋₂—C₁₋₆alkyl, —SO₂N(R^(b))R^(c), halo, —CF₃, —COOH, and —COOC₁₋₆alkyl; where R^(b) and R^(c) are each independently —H or —C₁₋₆alkyl; and where R^(d) is —H or —C₁₋₆alkyl; R³ is —CO₂C₁₋₄alkyl, or an aryl or heteroaryl group unsubstituted or substituted with one or two R^(e) substituents; where each R^(e) is independently —OH, —OC₁₋₆alkyl, —CN, —N(R^(f))R^(g), —C(O)N(R^(f))R^(g), —N(R^(h))C(O)R^(h), —N(R^(h))SO₂C₁₋₆alkyl, —C(O)C₁₋₆alkyl, —S(O)₀₋₂—C₁₋₆alkyl, —SO₂N(R^(f))R^(g), halo, —CF₃, —COOH, and —COOC₁₋₆alkyl; where R^(f) and R^(g) are each independently —H or —C₁₋₆alkyl; and where R^(h) is —H or —C₁₋₆alkyl; R⁴ is an aryl or heteroaryl group unsubstituted or substituted with one or two R^(i) substituents; where each R^(i) is independently —OH, —OC₁₋₆alkyl, —CN, —N(R^(j))R^(k), —C(O)N(R^(j))R^(k), —N(R^(l))C(O)R^(l), —N(R^(l))SO₂C₁₋₆alkyl, —C(O)C₁₋₆alkyl, —S(O)₀₋₂—C₁₋₆alkyl, —SO₂N(R^(j))R^(k), halo, —CF₃, —COOH, and —COOC₁₋₆alkyl; where R^(j) and R^(k) are each independently —H or —C₁₋₆alkyl; and where R^(l) is —H or —C₁₋₆alkyl; R⁵ is H or methyl; or R⁴ and R⁵ together form —(CH₂)₄—; M is lithium, sodium, or potassium, A is carbon or silicon; each R⁶ is independently C₁₋₄alkyl; and R⁷ is H or C₁₋₄alkyl.
 2. The process according to claim 1, wherein R¹ is phenyl, 4-cyanophenyl, 4-methoxyphenyl, 3,5-dichlorophenyl, naphthyl, or methyl.
 3. The process according to claim 1, wherein R³ is phenyl, 4-chlorophenyl, 4-methoxycarbonylphenyl, 4-nitrophenyl, 3-cyanophenyl, 4-methoxyphenyl, 4-dimethylaminophenyl, or ethoxycarbonyl.
 4. The process according to claim 1, wherein R⁴ is phenyl, benzo[1,3]dioxolyl, 2-chloro-6-fluorophenyl, 4-bromophenyl, 3-trifluoromethylphenyl, 4-nitrophenyl, 2-thienyl, 2-furanyl, or 3-pyridyl.
 5. The process according to claim 1, wherein R⁵ is H.
 6. The process according to claim 1, wherein strong base of formula (VI) is KOtBu.
 7. The process according to claim 1, wherein the solvent is THF.
 8. The process according to claim 1, wherein the strong acid is TFA, methanesulfonic acid, benzenesulfonic acid, or para-toluenesulfonic acid.
 9. The process according to claim 1, wherein the strong acid is TFA. 